Over the past two decades, advances in the practice of allogeneic hematopoietic cell transplantation (HCT) have resulted in decreased transplant related mortality (TRM), expanded access to older and/or medically at- risk populations, and the development of alternative approaches for patients without appropriately HLA- matched donors (unrelated cord blood [UCB] and haploidentical grafts), in addition, tantalizing hints of potentially beneficial novel cellular therapy approaches are appearing in single or limited center studies. Significant problems remain, however. Relapse is the largest cause for failure, and prevention of relapse and/or salvage therapies for relapse must be key goals of the BMT CTN moving forward. Graft-vs-host disease (GVHD) continues to cause unacceptable morbidity, especially In the expanding number of older patients receiving reduced intensity PBSC approaches. Alternative donor approaches are plagued with high rates of rejection and TRM. Finally, the success of HCT for non-malignant disorders using unrelated donor (URD) sources is limited by excessive GVHD, TRM, and rejection, and could benefit from disease-specific optimization of transplant approaches. The Pediatric Blood and Marrow Transplant Consortium (PBMTC), a group consisting 75 ofthe finest pediatric HCT centers in North America and Australia, Is uniquely qualified to address these important issues. The PBMTC has been one of the top Core Centers over the last two grant periods in patient accrual, data quality, laboratory compliance, and leadership. The PBMTC has collaborative agreements with the Children's Oncology Group (COG) and with the clinical trials arm of the Center for International Blood and Marrow Transplant Research (CIBMTR) that allow it to be a strong voice In the development of pediatric-focused trials and In providing developmental assistance and enrollment for combined pediatric/adult BMT CTN trials. The PBMTC proposal for this BMT CTN Core Center renewal grant seeks to optimize a highly immunoablative reduced Intensity preparative regimen for the treatment of hemophagocytic disorders. Preliminary data from PBMTC centers show promise of decreasing transplant related mortality from 35% to as little as 10% using the proposed regimen. The proposal contains significant biology questions focused upon decreasing GVHD, improving engraftment, defining optimal alemtuzumab dosing and dose timing, and correlating key genetic and immunologic measures with outcome. Success with this trial will change the standard of care for treatment of these diseases and lay the foundation for adaptation of similar approaches to other complex non-malignant conditions. RELEVANCE (See instructions): The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) should study novel approaches to prevent relapse, reduce graft vs. host disease, develop better alternative donor methods, and improve outcomes for patients with non-malignant diseases. The Pediatric Blood and Marrow Transplant Consortium (PBMTC) brings significant pediatric expertise and a proven track record to the BMT CTN. The PBMTC Core Center proposal alms to improve survival using a novel approach to treat hemophagocytic disorders.